Rapamycin and CTLA4Ig Synergize to Induce Stable Mixed Chimerism Without the Need for CD40 Blockade

Pilat, Nina; Klaus, Christoph; Schwarz, Christoph; Hock, Karin; Oberhuber, Rupert; Schwaiger, Elisabeth; Gattringer, Martina; Ramsey, Haley E.; Baranyi, Ulrike; Zelger, Bettina; Brandacher, Gerald; Wrba, Fritz; Wekerle, Thomas

doi:10.1111/ajt.13154

Cited by 27 publications

(24 citation statements)

References 74 publications

(88 reference statements)

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“…Increased regulatory activity might thus also provide a potential solution for the phenomenon of "split tolerance" seen in some chimeras, in which some types of grafts (e.g., BM) are accepted while other types (e.g., skin or heart) are rejected [20,72]. Tissuespecific minor antigens that have been identified to cause split tolerance in several models [73,74], are now known to be amenable to active regulation [20,41]. Thus, deliberately shifting the contributing mechanisms toward regulation indeed appears beneficial for the robustness of the state of tolerance achieved through mixed chimerism and increases the efficacy of such protocols.…”

Section: Regulatory Mechanismsmentioning

confidence: 99%

Section: Experimental Protocols Minimizing Conditioning Avoiding Globmentioning

confidence: 99%

“…As long as no effective anti-CD40L mAb is available for clinical use, its elimination from recipient conditioning would be desirable. Recently, the need for CD40 blockade was avoided by combining CTLA4Ig with rapamycin, which targets mTOR (mammalian target of rapamycin), thereby suppressing cell growth and proliferation (and low-dose irradiation with 2 Gy), which led to long-term multilineage mixed chimerism [20][21][22][23]. Notably, tolerance toward donor heart but not skin grafts was achieved in a fully mismatch combination (MHC plus minor histocompatibility antigen disparities), while tolerance toward donor heart and skin was observed in an MHC-mismatch only combination (without minor antigen disparities).…”

mentioning

confidence: 99%

“…Notably, tolerance toward donor heart but not skin grafts was achieved in a fully mismatch combination (MHC plus minor histocompatibility antigen disparities), while tolerance toward donor heart and skin was observed in an MHC-mismatch only combination (without minor antigen disparities). Thus, only a state of split tolerance was achieved lacking full tolerization of minor donor antigens [20].Costimulation blockade-resistant rejection remains a challenge, affecting the success rate of chimerism induction, which characteristically remains substantially below 100%, even in young naïve recipient mice [15]. NK cells are a major factor mediating costimulation blockade-resistant rejection by killing the target cells within 1 week [24, 25], but so are mature donor T cells when transferred as component of mPBSCs (instead of BMCs) [26].…”

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confidence: 99%

“…Intriguingly, the degree of tolerance achieved with Treg-cell therapy is more complete -despite incomplete clonal deletion -and more fully encompasses tolerance toward minor donor antigens, than without Treg-cell therapy [41]. Increased regulatory activity might thus also provide a potential solution for the phenomenon of "split tolerance" seen in some chimeras, in which some types of grafts (e.g., BM) are accepted while other types (e.g., skin or heart) are rejected [20,72]. Tissuespecific minor antigens that have been identified to cause split tolerance in several models [73,74], are now known to be amenable to active regulation [20,41].…”

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Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

et al. 2015

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Establishing donor-specific immunological tolerance could improve long-term outcome by obviating the need for immunosuppressive drug therapy, which is currently required to control alloreactivity after organ transplantation. Mixed chimerism is defined as the engraftment of donor hematopoietic stem cells in the recipient, leading to viable coexistence of both donor and recipient leukocytes. In numerous experimental models, cotransplantation of donor bone marrow (BM) into preconditioned (e.g., through irradiation or cytotoxic drugs) recipients leads to transplantation tolerance through (mixed) chimerism. Mixed chimerism offers immunological advantages for clinical translation; pilot trials have established proof of concept by deliberately inducing tolerance in humans.Widespread clinical application is prevented, however, by the harsh preconditioning currently necessary for permitting BM engraftment. Recently, the immunological mechanisms inducing and maintaining tolerance in experimental mixed chimerism have been defined, revealing a more prominent role for regulation than historically assumed. The evidence from murine models suggests that both deletional and regulatory mechanisms are critical in promoting complete tolerance, encompassing also the minor histocompatibility antigens. Here, we review the current understanding of tolerance through mixed chimerism and provide an outlook on how to realize widespread clinical translation based on mechanistic insights gained from chimerism protocols, including cell therapy with polyclonal regulatory T cells. Keywords: Clonal deletion Mixed chimerism Nonmyeloablative conditioning Transplantation tolerance Treg cells IntroductionLong-term outcome after organ transplantation has improved little in the past few decades and remains suboptimal [1]. Grafts are still lost to immunological damage that is not prevented by current immunosuppressive drug regimens [2], which in addition cause severe adverse effects, including increased risks of malignancy and infection. Therefore, immunological tolerance -i.e., a state of specific nonresponsiveness to donor antigens -remains the "Holy Grail" in clinical organ transplantation. Among the Correspondence: Dr. Thomas Wekerle e-mail: Thomas.Wekerle@meduniwien.ac.at numerous strategies that have been tested over time, chimerismbased tolerance induction appears particularly promising [3,4]. This concept is based on the cotransplantation of donor hematopoietic stem cells (HSCs) (contained in bone marrow (BM) or mobilized peripheral blood stem cells (mPBSCs)) into the organ transplant recipient who has been sufficiently preconditioned, either with radiation or cytotoxic drugs, to permit HSC engraftment. If engraftment is achieved, multilineage chimerism ensues, which is termed "mixed" chimerism if donor representation is clearly detectable (by flow cytometry, for instance) but is less than 100% (which would constitute "full" chimerism) and can be achieved with less extensive recipient conditioning.In 1945 Ray Owen described a naturally occur...

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Section: Regulatory Mechanismsmentioning

confidence: 99%

Section: Experimental Protocols Minimizing Conditioning Avoiding Globmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

et al. 2015

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Memory T cells are significantly increased in rejected liver allografts of rhesus monkeys

Kim

Lee

et al. 2018

Liver Transpl

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The rhesus monkey (RM) is an excellent preclinical model in kidney, heart, and islet transplantation that has provided the basis for new immunosuppressive protocols for clinical studies. However, there remain relatively few liver transplantation (LT) models in nonhuman primates. In this study, we analyzed the immune cell populations of peripheral blood mononuclear cells (PBMCs) and secondary lymphoid organs along with livers of normal RMs and compared them with those of rejected LT recipients following withdrawal of immunosuppression. We undertook 5 allogeneic ABO compatible orthotopic LTs in monkeys using 5 normal donor monkey livers. We collected tissues including lymph nodes, spleens, blood, and recipient livers, and we performed flow cytometric analysis using isolated immune cells. We found that CD4 or CD8 naïve T cells were normally seen at low levels, and memory T cells were seen at high levels in the liver rather than lymphoid organs or PBMC. However, regulatory cells such as CD4+ forkhead box P3+ T cells and CD8+ CD28– cells remained in high numbers in the liver, but not in the lymph nodes or PBMC. The comparison of CD4/8 T subpopulations in normal and rejected livers and the various tissues showed that naïve cells were dramatically decreased in the spleen, lymph node, and PBMCs of rejected LT monkeys, but rather, the memory CD4/8 T cells were increased in all tissues and PBMC. The normal liver has large numbers of CD4 regulatory T cells, CD8+ CD28–, and myeloid‐derived suppressor cells, which are known immunosuppressive cells occurring at much higher levels than those seen in lymph node or peripheral blood. Memory T cells are dramatically increased in rejected liver allografts of RMs compared with those seen in normal RM tissues. Liver Transplantation 24 256–268 2018 AASLD.

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Haploidentical Transplantation: Challenges and Solutions

Chakrabarti¹,

Jaiswal²

2021

Organ and Tissue Transplantation

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Rapamycin and CTLA4Ig Synergize to Induce Stable Mixed Chimerism Without the Need for CD40 Blockade

Cited by 27 publications

References 74 publications

Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

Memory T cells are significantly increased in rejected liver allografts of rhesus monkeys

Haploidentical Transplantation: Challenges and Solutions

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